Genoidentical Donor Research Articles

P-027: SICKLE CELL DISEASE AND AUTOIMMUNE LIVER DISORDERS: SHOULD HEMATOPOIETIC STEM CELL TRANSPLANTATION BE DISCUSSED EARLY?

Purpose: Patients with sickle cell disease (SCD) are prone to dys- or autoimmune disorders, such as autoimmune hepatitis (AIH), sclerosing cholangitis, or ulcerative colitis. Sclerosing cholangitis can develop in young children with an unusually severe course due to associated vaso-occlusion and ischemia. Liver transplantation may be indicated early but is a challenging procedure in SCD, with uncertain outcomes (Hurtova Liver Transpl 2011, Duvoux [abstract] JFHOD 2021). Hematopoietic stem cell transplantation (HSCT) can cure SCD, although conditioning may induce hepatic complications. Herein we report a series of 6 children with SCD and autoimmune disorders, 3 for whom liver or digestive symptoms resolved after successful HSCT, and 3 for whom cirrhosis precluded HSCT conditioning. Materials and methods: Of the 6 children (5 girls), 5 were HbSS and 1 was HbSC. Dysimmune symptoms appeared at a median age of 4.5 (3-12) years and were colitis (n=2), cerebral vasculitis (n=1), and AIH (n=3). In 4/6 patients, liver disease was an overlap AIH-sclerosing cholangitis, while 2/6 patients had either isolated AIH or sclerosing cholangitis. Liver biopsy showed cirrhosis in 3 patients. Median age at last follow-up (FU) was 13.5 (8-17) years. Results: The 3 patients without cirrhosis, including 2 with sclerosing cholangitis and dilated bile ducts, underwent HSCT with a geno-identical donor, at 6, 11.5 and 16 years old. Autoimmune disease was controlled with steroids, azathioprine, infliximab or cyclophosphamide with plasma exchanges and rituximab. Conditioning included hepatotoxic drugs busulfan (n=2) and treosulfan (n=1), with antilymphocyte globulins, fludarabine (n=3) and thiotepa (n=1). Transient hepatitis developed in 1 patient and moderate graft-vs-host disease (GVHD) in 2, which resolved after adapting immunosuppression treatment. HSCT was uneventful in the third patient. With a FU of 1 to 2.5 years, all 3 patients had no digestive or liver symptoms, normal or mildly elevated liver enzymes and unchanged liver imaging. The 3 patients with cirrhosis upon first visit, at ages 7, 8.5, 13 years old, were on regular exchange transfusions at last FU. One patient developed recurrent infectious cholangitis and received a liver transplant at age 10, with many complications; at 7 years of FU, sclerosing cholangitis relapsed and re-transplantation was discussed. Another had moderate portal hypertension, bilirubin levels of 100-200 µM, and prothrombin time 60%, on steroids. The third patient was on tacrolimus, had presented 2 episodes of reversible liver failure, bilirubin levels of 100 µM and prothrombin time 45% at last FU and had developed myasthenia. Conclusion: Autoimmune liver disease in children with SCD may rapidly lead to end-stage liver disease. Upon diagnosis, these disorders should be considered as severe complications of SCD and prompt early discussion of HSCT. HSCT should be performed before conditioning with hepatotoxic drugs is not feasible. If a geno-identical donor is not available, alternative donors could be considered (haplo-identical, unrelated). If the liver disease is not stabilized after HSCT, liver transplantation could be performed with a standard risk, in a patient rid of SCD. If liver transplantation must be performed before HSCT, HSCT could be discussed rapidly afterwards to avoid possible relapse of SCD-related liver disease and dysimmune liver disease. The authors do not declare any conflict of interest

Myeloproliferative neoplasms – a global view

Myeloproliferative neoplasms – a global view

Influence of hepatic Graft-Versus-Host-Disease (GVHD) on the pharmacokinetics of ciclosporin in a case of acute myeloid leukemia treated at the EHU Oran

Acute myeloid leukemia (AML) is a malignant blood disease that affects hematopoietic cells in the bone marrow. The best treatment for AML is allogeneic hematopoietic stem cell transplantation (HSC). To prevent and treat the main complication of allogeneic marrow transplant, graft versus host disease (GVHD), it is necessary to combine immunosuppressive therapy which includes ciclosporin (CsA). The objective of our work is to study the influence of hepatic GVHD on the pharmacokinetics of cyclosporin in an AMLcase. This is an allografted patient (CSH), presented to our Pharmacovigilance department at the EHU of Oran in Algeria, with the aim of carrying out therapeutic pharmacological monitoring (TPM) of ciclosporin. We proceeded to assay for residual ciclosporinaemia from D1 of the allogeneic transplant. The patient presented a fluctuation of the trough concentrations, the explanation of which was an onset of acute hepatic GVHD, confirmed by biopsy with an elevated hepatic function, which represents an incidence varying between 10 and 50% in patients receiving transplant from a genoidentical donor. Without forgetting the great inter-individual and intra-individual variability of the response to ciclosporin, the environmental and pathological factors and the numerous drug interactions which can be the cause of modification of the pharmacokinetics and the pharmacodynamics of this drug. In conclusion, the pharmacological monitoring of cyclosporin, which is the treatment of choice to prevent or treat GVHD, is mandatory due to its low therapeutic index and high inter- and intra-individual variability.

Health-Related Quality of Life at 1 Year in the Drepagreffe Trial Comparing Chronic Transfusion to Transplantation in Children with Sickle Cell Anemia and a History of Abnormal Cerebral Velocities

▪Health is not just defined as the absence of disease, but also as the state of physical, emotional, and social well-being. Sickle cell anemia (SCA)-children have poor health-related quality of life (HRQL), principally because of poor physical functioning and severe pain. Improving HRQL has become an important goal of medical care. We present here the results of HRQL at 1 year in the DREPAGREFFE trial.DREPAGREFFE, a French prospective, Mendelian randomized trial with 2 arms (transfusions/transplantation) defined by random-availability of a HLA-matched sibling, enrolled SCA-children younger than 15, regularly transfused for history of abnormal velocities by TCD, with at least one non-SCA sibling, and parents agreeing to HLA-typing and transplantation. Conditioning consisted of intravenous busulfan, cyclophosphamide and rabbit anti-thymocyte globulin. HbS was maintained below 30% when transfused. Between 12/2010 and 6/2013, 67 SCA-children (7 with stroke history) were enrolled. Thirty-two had a genoidentical donor and were transplanted, while 35 (no donor) were included in the transfusion arm. No stroke was observed during the 12-months follow-up. All transplanted patients successfully engrafted; three acute-GvHD (grade≥II) were observed, but none chronic-GvHD. All patients were alive at 1-year. Transplanted patients had the same hemoglobin electrophoresis as their donor and significantly lower median [IQR] cerebral velocity, and more had normalized velocities compared to the transfusion arm. However, no significant difference in cognitive performance was observed between the 2 arms at 1-year.HRQL at 1-year, was one of the trial secondary outcome. Data were collected using the PedsQL 4.0 Generic Core Scale, a generic HRQL questionnaire with a child self-report for aged 5 through 18 and a parent proxy-report for children aged 2 through 18. The scale contains 23 items assessing physical (8), emotional (5), social (5), and school functioning (5). Four composite scores (physical, emotional, social, and school functioning) were calculated. Scores ranged from 0 to 100, with the higher scores indicating higher HRQL.At 1 year, the child self-report showed significantly better scores in transplanted than transfused children for physical health (p=0.048) and school functioning (p=0.031) (Table). Significant differences were observed for items describing “hurt” (p=0.006) and “low energy” (p=0.021), and those about missing school due to “not feeling well” (p=0.029) or “going to the hospital” (p=0.001). The parent proxy-report showed highly significant better scores in transplanted children for all scales: physical (p<0.001), emotional (p<0.001), social (p=0.005) and school functioning (p<0.001).We show here that SCA-children have better physical health and school functioning after transplantation than on chronic transfusion, and that the differences observed concern the hurt, energy and school missings, while parents report strong differences for all items. Improvement of HRQL has been previously reported after transfusions at 3-years in a randomized trial (Silent Infarct Transfusion) (DeBaun 2014), and after transplantation in non-randomized study (Bhatia 2015), but this is the first randomized trial comparing transfusion to transplantation in SCA. It has been shown that parents usually report worse HRQL for their child than the child self-reports (Panepinto 2010) . This disagreement between parents and children has been reported to be related to parents' distress or disease severity. In contrast, in the present trial, parents of transplanted children reported a better HRQL than their child, suggesting better parental well-being, which is probably related to the better HRQL observed in their child and to anticipation of a better future. [Display omitted] DisclosuresPeffault De Latour:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Brousse:Add Medica: Membership on an entity's Board of Directors or advisory committees. Socié:Alexion Pharmaceuticals, Inc.: Consultancy.

The elusive gift

When the only geno-identical donor is a minor child with autistic type disorders, the question of consent arises. Reflection on the decision to transplant bone marrow in this specific context.

Plerixafor added to G‐CSF allows mobilization of a sufficient number of hematopoietic progenitors without impacting the efficacy of TCR‐alpha/beta depletion in pediatric haploidentical and genoidentical donors failing to mobilize with G‐CSF alone

Collection of a large number of early hematopoietic progenitors is essential for allogeneic apheresis products intended for TCR-alpha/beta depletion. We added plerixafor 0.24 mg/kg body weight (bw) on day 4 of high-dose filgrastim mobilization 10hours prior to apheresis in 16 (30.5%) pediatric allogeneic donors who failed to recover a sufficient number of CD34+ cells. On day 4 of G-CSF, the median CD34+ cell count in peripheral blood was 6 per μL (range 4-9 per μL) in 6 poor mobilizers and 16 per μL (range 12-19 per μL) in insufficient mobilizers. In all donors, the threshold of 50 CD34+ cells/μL was achieved, and the median increase was 14.8-fold in poor mobilizers and 6.5-fold in insufficient mobilizers, whereas it was 3.45-fold increase in those mobilized with G-CSF alone. In all donors, a predefined number of >10 × 106 CD34+ cells/kg of recipient bw before depletion was reached in the apheresis product. The use of plerixafor did not affect the purity of further TCR-alpha/beta depletion. Side effects were mild to moderate and consisted of nausea and vomiting. Thus, the safety and high efficacy of plerixafor was proven in healthy pediatric allogeneic hematopoietic cell donors.

New considerations in hematopoietic stem cell transplantation for severe combined immunodeficiency: how did newborn screening change our field, and can we finally brake the glass ceiling for haploidentical transplantation?

Pioneered in 1968, hematopoietic stem cell transplantation (HSCT) first cured a patient with severe combined immune deficiency (SCID) transplanted from a matched sibling, bringing hope for this previously fatal disease. Since then, HSCT has become the standard of care treatment for SCID with thousands of patients transplanted successfully worldwide. Initially successful mainly in patients with a matched sibling donor and in specific easier to transplant types of SCID, nowadays, most patients with SCID undergo successful transplantation due to HSCT technique advances. These include refined human leukocyte antigen (HLA)-tissue typing, use of alternative donors, availability of new stem cell sources such as umbilical cord blood, less toxic chemotherapeutic conditioning, as well as improved graft-versus-host disease (GvHD) prophylaxis. Other factors contributing to the success of transplantation include the improvement of supportive care by molecular detection of viral infections, enabling preemptive antiviral treatment before organ damage occurs. Increased awareness for primary immunodeficiency disorders (PID), leading to earlier diagnosis and referral to specialist centers, has been another important factor in successfully transplanting SCID patients. A major game changer in the last decade has been the implementation of neonatal screening for SCID. This increased early diagnosis, allowing for this disease to be almost universally diagnosed soon after birth in countries which included this test in their newborn screening program. As a result, early and optimal transplant timing and conditions could be achieved. However, very early diagnosis also raised new questions regarding SCID patients with a “leaky” phenotype, as well as dilemmas regarding transplant and conditioning regimens in very young infants. With improved diagnosis and treatment options, overall survival has increased to over 90% for SCID babies with a genoidentical donor and similar results are emerging for matched unrelated donor HSCT. Due to new advances, we hope to achieve similar results for those given HSCT from haploidentical donors as well. This review will focus on the new considerations in HSCT seen in recent years, and examines the effect they have had on treatment options and outcomes for SCID patients. Statement of novelty: The field of HSCT has advanced considerably since the first successful SCID bone marrow transplant in 1968. However, success rates have been limited due to delayed diagnosis and poor outcome of patients for which a HLA-matched donor could not be found. This review will discuss recent advances occurring in the last decade in HSCT for SCID, and our hopes to bring cure to this once fatal disease.

PF352 TUNISIAN FANCONI ANEMIA REGISTRY (TFAR) REPORT, THE 2018 UPDATE

Background:Fanconi anemia (FA) is a genetically and phenotypically heterogeneous inherited disease. Many groups have established FA registers. In Tunisia, we created, in collaboration with the Tunisian Fanconi Anemia Study Group (TFASG), the Tunisian Fanconi Anemia Registry (TFAR), already initiated in 1998, by retro and prospective registration of FA. The first report was published in 2012.Aims:We present here the update of Tunisan Fanconi Anemia Registry on 2018.Methods:All hematology and pediatrics departments include their FA patients diagnosed between January 1983 and April 2018. The diagnosis was based on the following criteria: before 1998, a progressive bone marrow failure, the malfomative syndrome (IFAR score greater than 2), spontaneous chromosomal instability +/‐ family history of FA. After 1998, it is based on chromosomal instability on exposure to mitomycin C (MMC) greater than 70% of mitoses. We analyzed epidemiological, clinical, biological features, treatment and evolution of the 232 patients included until 2018.Results:232 patients belonging to 157 families were included. The annual incidence was 6 cases / year. The mean age at diagnosis was 10 years 6 months, the median was 9 years (extreme: prenatal diagnosis to 41 years). The Geographic distribution shows predominance in the south and center of Tunisia (38% each) compared to the north (24%). The circumstances of discovery were anemic syndrome in 63% of patients, bleeding syndrome in 37% of patients, acute leukemia in 2% cancer in 0.8% of patients, and family survey in 9.5% of patients. There was consanguinity in 80%. Malformative syndrome in 78%: stature ponderal retardation in 71%, « café au lait » spots in 72%, facial dysmorphy in 85%, bone malformations 53%, thumb column anomalies 37% and renal malformations 57%. Pancytopenia at diagnosis was found in 56%: Thrombocypenia is the most constant hematologic anomaly 96%, anemia in 80% and leuconeutropenia is found in 73%. Elevation of fetal hemoglobin is found in 91% of cases.Among 232 patients, 58 patients have been allo grafted from matched geno identical donors: 56 brodherhood, 1 fadher and 1 grand fadher 68% of patients with donor. Five patients without geno identical donor, have been allografted: from pheno identical donors in four cases in France and one from phenoidentical cord blood in Germany.Androgen treatment was given in 141 mainly Norethandrolone. 79% of those patients were good responders at 12 months. Evolution to a myelodysplastic syndrome is observed in 26 patients 11% and to acute leukemia in 26 patients 11%: 21 AML and 5 ALL. Seven cancers is diagnosed in 6 patients 2.5%. The median survival age in all patients is 14 years 3 months, it is significantly better in allo grafted patients (19 years vs 13 years 6 months, p &lt; 0.00001). All cases of acute leukemia and cancer have died.Summary/Conclusion:FA seems frequent in Tunisia, which is in part explained by the high consanguinity and endogamy in our country. It is often severe or moderate and requires androgen treatment or bone marrow transplantation. It must concern all patients with matched related donor. We have not access to cord blood bank or international file of volunteer bone marrow donors to do phenoidentical allograft. We project to introduce the haplo identical related donor allograft for FA patients. All patients with solid tumor or acute leukemia have died. We must do prevention and early detection of cancer.

Design of the DREPAGREFFE trial: A prospective controlled multicenter study evaluating the benefit of genoidentical hematopoietic stem cell transplantation over chronic transfusion in sickle cell anemia children detected to be at risk of stroke by transcranial Doppler (NCT 01340404)

BackgroundChildren with sickle cell anemia (SCA) have an 11% risk of stroke by the age of 18. Chronic transfusion applied in patients detected to be at risk by transcranial Doppler allows a significant reduction of stroke risk. However, chronic transfusion exposes to several adverse events, including alloimmunization and iron overload, and is not curative. Hematopoietic stem cell transplantation allows termination of the transfusion program, but its benefit has not been demonstrated. DesignDREPAGREFFE (NCT01340404) is a multicenter, prospective trial enrolling SCA children younger than 15years receiving chronic transfusion due to a history of abnormal transcranial Doppler (velocities ≥200cm/s). Only those with at least one non-SCA sibling and parents accepting HLA-typing and transplantation with a genoidentical donor were eligible. Chronic transfusion was pursued in patients with no available donor, whereas others were transplanted. Comparison between the 2 arms (transfusion vs transplantation) was analyzed using both genetic randomization and propensity-score matching as a sensitivity analysis. The primary end-point was the velocity measure at 1year. Secondary endpoints were the incidence of stroke, silent cerebral infarcts and stenoses, cognitive performance in comparison with siblings, allo-immunization, iron-overload, phosphatidyl-serine, angiogenesis/hypoxia, brain injury-related factor expression, quality of life and cost. ObjectivesTo show that genoidentical transplantation decreases velocities significantly more than chronic transfusion in SCA children at risk of stroke. DiscussionDREPAGREFFE is the first prospective study to evaluate transplantation in SCA children. It compares the outcome of cerebral vasculopathy following genoidentical transplantation versus chronic transfusion using genetic randomization and causal inference methods.

Allogeneic/Matched Related Transplantation for β-Thalassemia and Sickle Cell Anemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure single gene disorders such as thalassemia and sickle cell anemia (SCA). These non-malignant diseases have in common severe hemolytic anemia and high proliferative bone marrow, requiring frequent transfusions. The risk of rejection is high and graft-vs-host disease is not desirable. Important progress has been made in the management of these diseases, including leukocyte depletion of blood products, and chelation therapy, for both diseases, and erythrocytapheresis and hydroxycarbamide for SCA. However, morbidity and quality of life are still of concern. Results have also significantly improved for HSCT, with the reduction of rejection by using anti-thymocyte globulin (ATG), which also decreases the risk of chronic graft-vs-host disease. Current data show a more than 90% chance of cure with myeloablative conditioning in children with hemoglobinopathy and a geno-identical donor. Results are similar whether the cell source is cord blood or bone marrow. Because of the risk of conditioning-related infertility, ovarian and/or testis cryopreservation should be discussed. Non-myeloablative conditioning regimens have also been successfully developed in adults with SCA and organ dysfunction, making cure possible. These encouraging results should incite to perform HLA typing early in families with hemoglobinopathies, and to systematically propose sibling cord blood cryopreservation for those without geno-identical donor.

Donor-Specific Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of human leukocyte antigen (HLA) incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of primary graft failure (PGF), a severe complication of AHSCT that occurs in 3–4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 and 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect donor-specific antibodies (DSA) in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field.

Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities

AbstractStroke risk in sickle cell anemia (SCA), predicted by high transcranial Doppler (TCD) velocities, is prevented by transfusions. We present the long-term follow-up of SCA children from the Créteil newborn cohort (1992-2012) detected at risk by TCD and placed on chronic transfusions. Patients with normalized velocities and no stenosis were treated with hydroxyurea, known to decrease anemia and hemolytic rate. Trimestrial Doppler was performed and transfusions restarted immediately in the case of reversion to abnormal velocities. Patients with a genoidentical donor underwent transplant. Abnormal time-averaged maximum mean velocities (TAMMV) ≥200 cm/s were detected in 92 SCA children at a mean age of 3.7 years (range, 1.3-8.3 years). No stroke occurred posttransfusion after a mean follow-up of 6.1 years. Normalization of velocities (TAMMV < 170 cm/s) was observed in 83.5% of patients. Stenosis, present in 27.5% of patients, was associated with the risk of non-normalization (P < .001). Switch from transfusions to hydroxyurea was prescribed for 45 patients, with a mean follow-up of 3.4 years. Reversion, predicted by baseline reticulocyte count ≥400 × 109/L (P < .001), occurred in 28.9% (13/45) patients at the mean age of 7.1 years (range, 4.3-9.5 years). Transplant, performed in 24 patients, allowed transfusions to be safely stopped in all patients and velocities to be normalized in 4 patients who still had abnormal velocities on transfusions. This long-term cohort study shows that transfusions can be stopped not only in transplanted patients but also in a subset of patients switched to hydroxyurea, provided trimestrial Doppler follow-up and immediate restart of transfusions in the case of reversion.

French National Drepagreffe Trial: Cognitive Performances and Neuroimaging at Enrollment and after 12 Months on Transfusion Program or Transplantation (AP-HP: NCT 01340404)

Background: "Drepagreffe" is a French national prospective trial involving 67 sickle cell anemia (SCA)-children with a history of abnormal cerebral arterial velocities by TCD, and comparing for the first time the outcome of cerebral vasculopathy following transfusion program (TP) or transplantation (HSCT). Inclusion criteria at enrollment were children with SCA (SS/Sb0), younger than 15 years, with a history of abnormal cerebral arterial velocities (TAMMX ≥ 200 cm/sec) and placed on long-term TP, with at least one non-SCA sibling, and with parents accepting HLA-typing and HSCT if a genoidentical donor was available. The 2 arms (TP/HSCT) were defined by the random-availability of a genoidentical donor. Seven of the 67 patients had a history of stroke. Transplanted patients (n=32) received a conditioning regimen of Busilvex-CY 200 mg/kg and 20 mg/kg rabbit Thymoglobulin, with CSA and a short course of MTX or MMF for GvHD prophylaxis. In the TP arm (n=35), HbS% was maintained at < 30%, with an Hb at 9-11g/dL. At enrollment and 12 months post-enrollment, blood screening, Doppler, and cerebral MRI/MRA were performed along with cognitive performance testing, the latter being done in parallel in the non-SCA siblings. Preliminary findings on cerebral velocities as the primary endpoint were reported at the last ASH meeting (abstract 67237), and demonstrated that all patients were alive at one year and that the 32 transplanted patients had no chronic GVHD and the same hemoglobin profile as their donor. Velocities were significantly lower post-HSCT than under TP (p <0.001), and were normalized in a greater number of patients (p =0.003).Patients and Methods: We report here the cerebral imaging (MRI/MRA) and cognitive performance data performed at enrollment and after 12 months. The scoring applied for MRI was: 3 = territorial, 2 = borderzone (cortical and subcortical), 1 = white matter or basal ganglia infarcts, 0 to 3 = atrophia, and for MRA: 1 = mild stenosis (25-49%), 2 = moderate stenosis (50-74%), 3 = severe stenosis (75-99%), 4 = occlusion for each artery and 0 to 2 for Moya presence. Cognitive testing using the WPPSI-3 (3-6 yr), WISC-4 (7-16 yr) or WAIS-3 (>16 yr) scales, depending on the age, was performed in patients and in siblings when possible.Results: MRI/MRA data were available in 66/67 patients. At enrollment (M0), ischemic lesions and stenoses were present in 25 and 35/66 patients, respectively. Cognitive testing was obtained in 64 patients and 56 siblings. Paired analysis with siblings (Table 1) showed significant differences in Verbal Comprehension Index (VCI) with a mean difference of 7.6±14.5(p =0.0004), Processing Speed Index (PSI) 6.3±20.5 (p =0.04), and Full Scale IQ (FSIQ) 7.3±15.0 (p =0.01). After exclusion of the 7 patients with stroke history, significant differences were still observed in VCI (p =0.013) and FSIQ (p =0.019). Patient cognitive performance indexes were correlated negatively and significantly with the MRI and MRA scores (Table 2). At post-enrollment (M12),ischemic lesions and stenoses were present in 26/66 patients. The mean variation in MRI and MRA scores between M12 and M0 was not significantly different between the 2 arms (Table 3). The cognitive tests were performed at M12 in 60 patients (Table 4) and the performance indexes were improved in the TP compared to the HSCT arm, but only significantly for FSIQ.Conclusion This first prospective trial initially showed that HSCT reduces more significantly the cerebral velocities at M12 and in a higher proportion of patients than TP. Here, we show that patients with a history of abnormal cerebral velocities had significantly lower cognitive performances than their siblings, even in the absence of stroke history; however, there was no significant difference between the 2 arms for the outcomes of ischemic lesions and stenosis at M0 and M12. The fact that cognitive performances were improved in the TP compared to the HSCT arm might be explained by the stress of the HSCT procedure and the lack of schooling during this period. Despite the higher ability of HSCT to decrease velocities at M12 compared to TP, a longer follow-up will be required to demonstrate its effect on stenosis and cognitive performances; therefore, patients will be reassessed at 3 years post-HSCT. [Display omitted] DisclosuresBernaudin:Novartis: Research Funding.

T-cell-replete haploidentical transplantation versus autologous stem cell transplantation in adult acute leukemia: a matched pair analysis.

Adult patients with acute leukemia in need of a transplant but without a genoidentical donor are usually considered upfront for transplantation with stem cells from any other allogeneic source, rather than autologous stem cell transplantation. We used data from the European Society for Blood and Marrow Transplantation and performed a matched pair analysis on 188 T-cell-replete haploidentical and 356 autologous transplants done from January 2007 to December 2012, using age, diagnosis, disease status, cytogenetics, and interval from diagnosis to transplant as matching factors. "Haploidentical expert" centers were defined as having reported more than five haploidentical transplants for acute leukemia (median value for the study period). The median follow-up was 28 months. Multivariate analyses, including type of transplant categorized into three classes ("haploidentical regular", "haploidentical expert" and autologous), conditioning intensity (reduced intensity versus myeloablative conditioning) and the random effect taking into account associations related to matching, showed that non-relapse mortality was higher following haploidentical transplants in expert (HR: 4.7; P=0.00004) and regular (HR: 8.98; P<10(-5)) centers. Relapse incidence for haploidentical transplants was lower in expert centers (HR:0.39; P=0.0003) but in regular centers was similar to that for autologous transplants. Leukemia-free survival and overall survival rates were higher following autologous transplantation than haploidentical transplants in regular centers (HR: 1.63; P=0.008 and HR: 2.31; P=0.0002 respectively) but similar to those following haploidentical transplants in expert centers. We conclude that autologous stem cell transplantation should presently be considered as a possible alternative to haploidentical transplantation in regular centers that have not developed a specific expert program.

Cerebral Arterial Velocities in SCA-Children with Abnormal Doppler Are Reduced and Normalized More Frequently after Transplantation Than after Transfusion Program (French National Trial “Drepagreffe” AP-HP N°: NCT 01340404)

Background: Evidence-based practices have shown that transfusion program (TP) is beneficial to SCA-patients with abnormally high velocities by Doppler; however, TP cannot be stopped safely, except following HSCT. No prospective trial has to date compared the extent of cerebral vasculopathy following TP or HSCT. The premise of the French National Trial “Drepagreffe” is that cerebral velocities will be reduced to a greater extent after HSCT than under TP.Patients and Methods: We present here preliminary results from this prospective trial with 2 arms (TP/HSCT), defined by the random-availability of a genoidentical donor. Inclusion criteria were SCA (SS/Sb0) children younger than 15 years with a history of abnormal cerebral arterial velocities (TAMMX ≥ 200 cm/sec), placed on long-term transfusion programs, with at least one non-SCA sibling and parents accepting HLA-typing and HSCT if a genoidentical donor was available. Transplanted patients received as conditioning regimen Busilvex-CY 200 mg/kg and 20 mg/kg rabbit Thymoglobulin with CSA and short MTX or MMF for GVHD prophylaxis. In the TP arm, HbS% was maintained at < 30% with Hb 9-11g/dL. At enrollment and 12 months post-enrollment, blood screening, Doppler, cerebral MRI/MRA were performed along with cognitive performance testing, the latter done in parallel in the control sibling. Primary endpoint was the significantly greater reduction of velocities in the HSCT than in the TP arm. Among the various secondary endpoints, Doppler normalization defined by velocities < 170 cm/s in all arteries was to occur more often after HSCT than on TP.Results: SCA-children (n=67; 36F-31M) from 10 French SCA-centers were enrolled between 12/2010 and 6/2013 at the mean (SD) age of 7.6 (3.1) years. History of stroke was present in 6 patients (4 in HSCT and 2 in TP) and 1 TIA in HSCT arm. At TP initiation, velocities≥200/cm/sec were found in middle (n=50), anterior (n=11) and internal carotid arteries (n=30) as abnormal velocities were observed in more than one artery in several patients. Mean (SD) maximum velocities were 219 (26) cm/s (range: 200-333). At enrollment all patients were on TP and paired analysis showed that mean(SD) maximum velocities had significantly decreased (p<0.001) under TP:169 (46) cm/s vs 219 (26) cm/s). Following HLA-typing, 35 without genoidentical donor were included in the transfusion arm and 32 with genoidentical donor were transplanted in 6 HSCT-centers. Mean (SD) maximum velocities were not significantly different in both arms at enrollment: 167 (41) in TP vs 170 (51) cm/s in HSCT. During the 12 months follow-up, no stroke was observed but one patient in the TP arm experienced a hyperammonemic reversible coma, without MRI/MRA alteration requiring transfer to intensive care. In the HSCT arm, all patients successfully engrafted, one grade II and two grade III acute GVHD, and no chronic GVHD were observed. Two patients required transfer to intensive care for seizures and pneumonia. Other complications were seizures (n=2), CMV (n=9) or EBV replications (n=1), hemorrhagic cystitis (n=3), aspergillosis (n=1), prolonged but reversible thrombopenia (n=2), transitory hemolytic anemia (n=1). At 12 months, data, available in 63/67 patients, showed that all patients were alive, mean (SD) Hb and HbS% in TP arm were 9.1 (0.9) and 27.5% (11.9), respectively, whereas in the HSCT arm, mean (SD) Hb and % donor chimerism were 12.0 (1.0) g/dL and 86.5% (12.2) respectively (range:60-100%). All transplanted patients had the same Hb electrophoresis than their donor. Mean (SD) maximum velocities were significantly lower post-HSCT (n=31) than under TP (n=32):128 (34) vs 174 (36) cm/s, respectively; (p<0.001), and were decreased more significantly following HSCT than on TP: mean(SD)Δ: -44 (24) vs +6 (3), respectively. The percentage of patients with normal velocities was significantly higher post-HSCT (27/31) than in the TP arm (16/32) (p=0.003).Conclusions: This prospective national trial comparing TP vs. HSCT in SCA-patients with a history of abnormal velocities shows for the first time that HSCT repeatedly and significantly results in a greater decrease in velocities than TP, and has very little toxicity. These preliminary results are encouraging and suggest that suppression of host SCA-erythropoiesis by HSCT is the treatment of choice for SCA-children with abnormal-TCD and genoidentical donor. [Display omitted] [Display omitted] DisclosuresBernaudin:Novartis: Research Funding.

Haploidentical Versus Autologous Stem Cell Transplantation in Adult Acute Leukemia: A Matched Pair Analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Adult patients with acute leukemia in need of a transplant but with no genoidentical donor, are nowadays usually considered upfront for an alternative donor transplant, while autologous stem cell transplantation is seldom done. The purpose of this study was to compare the outcome after T cell-replete haploidentical transplant and autologous transplant. We used data from the European Society for Blood and Marrow Transplantation (EBMT) registry. From January 2007 to December 2012, 234 adult patients with acute leukemia, transplanted with marrow from a haploidentical family donor, and 2259 autografted patients were reported to the EBMT registry. We performed a matched pair analysis on 188 haploidentical and 356 autologous transplants using age, diagnosis, disease status, cytogenetics, and interval from diagnosis to transplant as matching factors. The median follow-up was 15 months.The two-year non-relapse mortality rate was higher post-haploidentical transplant ( 27% versus 4%; p <10-5 ) [hazard ratio (HR): 0.16, p<0.0001], and the relapse incidence was higher after autologous transplantation ( 49% versus 31%, p <10-4) (HR: 1.69, p=0.02). Regarding LFS, there was no difference between haploidentical transplants and ASCT (Figure 1 A and 1 C). Overall survival was higher after autologous transplantation (HR: 0.69, p=0.02) with 63% versus 53% (p=0.01) in all patients, 67% versus 54% (p=0.006) in patients transplanted in first complete remission (Figure 1B), and 45% versus 47% in second complete remission (Figure 1 D). Thirty-six patients with Ph+ ALL received an autograft and 19 received a haploidentical transplant. ASCT was associated with better NRM (8% versus 46%; p=0.002), LFS (53% versus 22%; p= 0.01), and OS (70% versus 19%; p 0.001), while RI was identical (39% versus 32%; p=0.83).When comparing haploidentical transplants performed in “haplo expert” centers to ASCT, there was no difference in LFS (haplo: 53% versus ASCT 46%, p=0.17) and OS (haplo: 59% versus ASCT 63%, p=0.58) (Figure 2).These findings indicate that autologous stem cell transplantation remains a valuable therapeutic option for patients with no identical donors. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Relevance of a One-Year Maintenance Therapy with Interleukin-2 in the Treatment of Childhood Acute Myeloid Leukemia: Results from the French Multicenter, Phase III, Randomized Controlled Sfce Trial, ELAM02

▪Background: Childhood acute myeloid leukemia (AML) remains a challenging disease as the outcome is still poor despite major improvement over the past decades; current survival rates are around 70% but event free survival (EFS) is only about 50%. No benefit of standard maintenance chemotherapy has been proven after intensive induction/consolidation chemotherapy.Objective: To determine whether the addition of a one-year maintenance therapy using interleukin-2 (IL-2), known to stimulate antitumor immunity, decreases the risk of relapse and improves EFS in pediatric AML.Methods: ELAM02 trial was designed to recruit patients aged from 0 to 18 years, diagnosed with primary AML. Children with acute promyelocytic leukemia and Down Syndrome were not included. The treatment consisted of one induction course (cytarabine and mitoxantrone) and three consolidation courses (course 1 and 3 with high dose cytarabine); all children without t(8;21) were candidates for hematopoietic stem cell transplant (HSCT) in complete remission (CR) after 1 to 2 courses of consolidation if a geno-identical donor was available; children with poor-prognosis karyotype were also candidates for HSCT with pheno-identical donor.The patients not receiving HSCT and in continuous CR after the third course of consolidation were eligible for randomization for a one-year maintenance therapy consisting in monthly courses of IL-2. IL-2 (Proleukin®, Chiron, Novartis) was given subcutaneously at 2.5 MUI/m² on day 1 and at 5 MUI/m² from day 2 to 5. Cycles were planned to be given monthly for up to 12 cycles. In case of side effects such as severe (grade ≥ 3) clinical toxicities (fever >40°C, hypotension requiring IV fluids) and/or severe biological toxicities (thrombocytopenia (grade ≥ 3), renal dysfunction (grade ≥ 2), liver dysfunction (grade ≥ 3)) doses of IL-2 was lowered of 50%. In case of persistent side effects, treatment was discontinued. The control group received no maintenance treatment.Results: The 28 French SFCE centers participated to the study, leading to the enrollment of 441 patients from March 2005 to December 2011. Among the 441 enrolled patients, 3 patients were excluded due to non-conformity of inclusion criteria; 392/438 (89%) were in CR after the first consolidation course and 116 (30%) were allografted in CR1. Out of the 241 eligible patients for randomization, i.e. still in CR after the third course of consolidation, 154 (64%) were actually randomized for maintenance therapy; causes for non-randomization were either parents refusal (n=50, 21%) or medical decision (n=37, 15%). Median follow-up is 5 years. The characteristics of the randomized patients at diagnosis were as follows: [Display omitted] Median number of IL-2 cycles administered was 12 [5-12], the mean being 8.6 ± 4.2. Among the 77 patients receiving maintenance therapy, IL-2 was stopped before cycle 6 in 20 patients (26%) and after cycle 6 in 18 (23%); 39 patients (51%) received 12 cycles. Treatment was stopped because of relapse occurrence (n=15), severe persistent toxicities (n=6) or parents or medical decision (n=17). The most frequent toxicities related to IL-2 treatment were fever, chills, and cytolytic hepatitis; no toxic death related to IL-2 therapy was observed. Incidence of relapses in IL2+ group and IL2- group were 36% (n=28) and 38% (n=29) respectively. The 5-year disease free survival (DFS) was 62 % (95% CI 51-73) for the IL2- group vs. 64% (95% CI 53-75) for the IL2+ group (p=0.74). Among the CBF population, a trend in favor of the IL-2 treatment was observed as the 5-year DFS was 57% (95% CI 43-71) for the IL2- group vs. 78% (95% CI 63-94) for the IL-2+ group (p=0.08).Conclusion: A prolonged administration of IL-2 as maintenance therapy after intensive chemotherapy is feasible in pediatric AML patients in first CR but did not improve DFS in this study. DisclosuresNo relevant conflicts of interest to declare.

Pharmacokinetics/Pharmacodynamic Relationship in Busulfan Conditioning Regimen: Results from a Large Pediatric Cohort Undergoing Hematopoietic Stem-Cell Transplantation

▪Background: Busulfan (Bu) is the corner stone of hematopoietic stem-cell transplantation (HSCT) regimens with a narrow therapeutic window (TW). Graft rejection or toxicities are reported according to plasmatic exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability. Bu clearance was demonstrated to be non-linearly related to body weight (BW) and thus BW is used to optimally define the Bu dosage in children [Vassal et al., CCP 2006]. Search for additional data to confirm the TW and to describe clinical outcomes is still a topical question to better understand Pk/Pd relationship and to safely use Bu in young children and infants.Objective: To study the Pk/Pd relationship of Bu in pediatric recipients of bone marrow transplantation (BMT) receiving Bu-based conditioning regimens (CR). To correlate early toxicities (mainly hepatic veno-occlusive disease (VOD), non infectious pulmonary disease (niPD) and outcome i.e. overall survival (OS) at last follow up with type of CR, the underlying diseases, age at transplantation and Pk of busulfanPatients and Method: This multicenter prospective observational study included 307 pts transplanted between 2006 and 2013 from 14 French Pediatric BMT units; median age at transplantation was 18.4 months [1.3-289], with a median BW of 11.3 kg [3.4-82]. 100 pts were younger than 1 year, 71 pts < 9 kg and 171 pts < 16 kg. Patients were mostly affected by non-malignant diseases (primary immune deficiency (n=143), inherited metabolic disorders (n=50), hemoglobinopathies (n=20) while 78 patients suffered from malignant disease. 257 patients received allogenic HSCT (genoidentical donor n=79, matched unrelated donor n=33, mismatch unrelated donor n=18, haploidentical intra-familial donor n=59, other mismatched intra familial donor n=8 or unrelated cord blood n=51) and 41 autologous BMT. All patients received Bu-based conditioning regimen in combination with cyclophosphamide (BuCy n=119), fludarabine (BuFlu n=88), melphalan (BuMel n=36) or thiotepa (BuTTP n=3). 40 patients received BuFlu associated with a second alkylating agent (Mel, TTP or Cy), 12 patients received BuCy associated with a third agent (Mel or VP16). Serotherapy was given in 70% of the patients. Starting doses of Bu were given according to the European SmPC or EBMT-ESID recommendations. The median posology was 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg].PK was assessed on plasma samples with area under the curve (AUC) evaluation from the 1st(D1), 9th (D9) and 13th (D13) dose in 150 patients, D1 and D9 in 40 patients, D1 and D13 in 46 patients while 62 patients were monitored on D1 only (684 PK datasets). PK analysis was performed using Non linear Mixed Effect Modelling. A one-compartment PK model suitably fitted the concentrations vs time data. Median follow up is 27 months (0.33 to 96 months post BMT).Results: At D1, 67% of patients were within the therapeutic window (TW) [900-1500 µM.min] and 66% of patients reached the cumulative TW [14400-24000 µM.min]. Incidence of VOD and niPD were respectively 35% and 14%. Both toxicities correlated with type of CR and age <1 year at transplantation. Incidence of aGVH was 33%. However, these incidences were very different according to the CR. BuFlu showed the lowest incidence compared to other combinations of drugs (p < 0.001 and =0.022 for VOD and niPD, respectively). When using a second alkylating agent, incidence of VOD reached 41% (vs 19% in BuFlu, p<0.001) and niPD 17% (vs 8% in BuFlu, p<0.040). Toxicities were also related to BW, with 48% vs 30% (p<0.013) for VOD below or above 9 kg, and respectively, 28% vs 9% (p<0.0002) for niPD. This tendency was also found with a 15 kg cut-off for aGVH. No correlation was found with Bu AUC. However, there was a trend for lower OS (HR 1.60 [1.00-2.58], p=0.051) in patients with AUC D1 <900 µM.min compared to patients with AUC D1 > 900 µM.min. OS was 69.1% at last follow up and was not significantly associated with CR and age at transplantation.Conclusion: In this large series of pediatric BMT recipients, we found that toxicities as VOD and niPD correlated with type of CR and age at transplantation in univariate analysis. Combination of 2 alkylating agents with Bu or BuFlu and transplantation < 1 year of age were associated with the highest incidence of toxicites. The TW targeting performance was improved in this cohort compared to previous reported data (Paci et al. TDM 2012). Specific TW for each group of pathologies will be proposed. DisclosuresNo relevant conflicts of interest to declare.

Early Clinical Manifestations, Presence Of a Single Bantou Haplotype and High Baseline Reticulocyte Count Predict Severity In a Sickle Cell Anemia Newborn Cohort

IntroductionSickle cell anemia (SCA) is a monogenic disease with multigenic expressivity. The ability to identify high-risk SCA-children would permit accurate prognostication and better genetic counselling, and facilitate the planning of clinical trials. Miller et al. (CSSCD) reported in 2000 that early dactylitis, baseline Hb level<7g/dl, and leukocytosis correlated significantly with adverse outcomes later in life. However, Quinn et al. reported in 2007 in the Dallas newborn cohort that none of the events before age 3 predicted death or stroke after age 3. Patients and MethodsThis study revisits this issue using the Créteil Newborn Cohort (1986-2011). The dates and nature of the 1st SCA-related manifestations and further clinical events were prospectively recorded: vaso-occlusive crises (VOC) including dactylitis, acute chest syndromes (ACS), strokes, splenic sequestrations and acute anemia < 6g/dl. Alpha-genes, beta-globin haplotypes, G6PD activity, CD36 platelet expression were determined and baseline biological parameters (WBC, PMN, platelets, Hb, Hct, MCV, reticulocytes, HbF%, LDH) were recorded between 1-2 years of age, a minimum of 3 months away from a transfusion, one month from a painful episode and before any intensive therapy. The criteria of severity retained for this study were death or events requiring intensive therapy, defined as hydroxycarbamide (HC) prescribed for patients having experienced at least 3 VOC/year or 2 ACS or with baseline Hb<7g/dl; transfusion program (TP) for those with recurrent splenic sequestrations or strokes or abnormal velocities on Doppler (TCD); stem cell transplantation (HSCT) for those with indication of intensive therapy and genoidentical donor. Cox regression was used to analyze the predictive factors of severity. ResultsThis newborn cohort consists of 363 patients (55 SC,28 Sb+,262 SS,15 Sb0,3 SDPunjab). Median age at last visit was 6.4 years, providing 2827 patient-years of follow-up. As no SC or Sb+ patient died or experienced events requiring intensive therapy, analysis of severity criteria was only performed on SS, Sb0, SDPunjab, referred as SCA-patients (n=280). Alpha-thalassemia was present in 41.6%, Bantou/Bantou beta haplotype in 43.4% (vs 5.9% in the CSSCD cohort), Benin/Benin in 22.9%, Senegal/Senegal in 10.2%, “other” in 23.4%. G6PD deficiency was observed in 11.4% and CD36 non-expression in 7%. Kaplan-Meier estimates of survival by age 5 and 18 were 97.6% (95%CI:95.6-99.6%). One-hundred-fifty-one/280 SCA-patients (54%) required intensive therapy at the median age of 3.8yr (0.1-20): 69 HC, 136 TP, and 41 HSCT (patients may have successively received HC, TP and HSCT). Cumulative risk of severity criteria was 45% by age 5 and 70% by age 10. Univariate Cox analysis showed that Bantou presence (52.6%), CD36 non-expression, early SCA-1st manifestation (<1 and <3 year of age), baseline high level of WBC, reticulocytes and LDH, low levels of Hb and Hct were significantly associated with severity whereas platelets, HbF, MCV, alpha genes number and G6PD were not. Multivariate Cox analysis retained as significant and independent predictive risk factors for severity: high reticulocyte level (>400x109/L) (HR=2.82,95%CI:1.70-4.69,p<0.001); the presence of a single Bantou haplotype (HR=1.76,95% CI:1.18-2.60,p=0.007); and early (<1 year of age) first SCA-clinical manifestation (HR=2.35,95%CI:1.55-3.56,p<0.001). ConclusionThis study confirms Miller's report, showing that the risk level can be estimated by age 2 in SCA-patients, a result potentially useful for prospective trials (HC/HSCT). Moreover, we show for the first time that the presence of a single Bantou haplotype has predictive value for severity in this cohort where its frequency is much higher than in the CSSCD cohort. [Display omitted] Disclosures:Bernaudin:Novartis: Research Funding.

Sickle Cell Anemia and HSCT: Relation Between ATG, Chimerism, Gvhd and Outcome In Myeloablative Genoidentical Transplants For The SFGM-TC

BackgroundSickle Cell Anemia (SCA) remains a disease with high risk of morbidity and early death. HSCT is currently the only curative treatment for SCA, but its use has been limited by the risks of transplant-related mortality (TRM) and GVHD. We have previously demonstrated that antithymocyte globulin (ATG) efficiently decreases the rejection rate in HSCT for SCA; however, its optimal dose has not been defined, prompting us to retrospectively analyse outcomes in patients from the SFGM-TC cohort receiving different ATG doses. Patients and MethodsThe cohort includes 236 SCA-patients (109F, 127M), (229 SS, 5 Sb0, 2 SDPunjab) transplanted in France (1988-2012) with geno-identical donors after homogeneous myeloablative conditioning regimen (CR; BU-CY), and rabbit ATG (n=215) at 5-15 mg/kg (n=35), 20 mg/kg (n=160) or no ATG (n=20). Cell sources were bone marrow (BM, n=197), cord blood (CB, n=30), CB+BM (n=8), and peripheral blood cells (PBC, n=1). Chimerism was assessed by quantitative real-time PCR from PBC at Day-30, 60, 90, Month-6, 12 and every year post-transplant, and defined as total donor chimerism (TDC): >95% donor (D); low (5-50%D) or high (50-95%D) mixed chimerism (MC),; or rejection (< 5%D). Disease-free survival (DFS) was defined as the absence of HSCT-related death and rejection. GVHD prophylaxis consisted of CSA-short MTX for BMT and CSA alone for CBT.ResultsMean age at transplant was 9.7yr (range: 2.2-28.9), with 33 patients older than 15. With a mean follow-up of 5.6yr (range 0.5-22.5), TRM was not different with or without ATG (3.4%; 0.8-6%) whereas DFS was higher (p=0.004) with ATG (95.4%; 92-4-98.4) than without (72.7%; 51.7-93.7), due to differences in rejection rates (p<0.001). DFS was similar whether the cell source was CB or BM. No lymphoma was observed, and only one post-transplant death at 5m was virus-related (adenoviral meningo-encephalitis). Incidences of AGVH ≥2, 3-4 and chronic-GVHD (cGVHD) were 19%, 6% and 8.7%, respectively. Univariate Cox analysis showed that significant risk factors affecting DFS were low dose of ATG, AGVH grade, and cGVHD, whereas cell source, ABO compatibility, donor's and recipient's (DR) age, and CMV status were not. Risk factors associated with cGVHD (Logistic regression) were ATG dose (20% incidence with no ATG, 15.6% with 5-15 mg/kg and only 6.4% with 20), DR age (even after exclusion of CBT), whereas DR genders, DR CMV status, and cell source doses (NC, CD34, CD3+) were not. Multivariate analysis only retained ATG dose (OR=0.9/mg/kg increase, 95% CI:0.8-1, p=0.007) and donor's age>15 (OR=7.9, 95%CI: 2.5-25.6,p<0.001) as significant independent risk factors for cGVHD. Chimerisms (n=165) (Figure) were significantly associated with ATG dose and cGVHD occurrence. Among the 6 patients with low MC at 1yr, 3 had not received ATG and rejected at 2, 2.2 and 8yr post-HSCT whereas the 3 others who had received ATG remained stable. All patients with high MC at 1yr (n=54) and TDC (n=80) are doing well with the same electrophoretic profile as their donor, excepted one patient who experienced appearance of MC with hemolysis (D/R group U+/U-) 5yr post-CBT, requiring donor lymphocyte infusion (DLI), which reversed chimerism to TDC but induced cGVHD. [Display omitted] ConclusionThis study confirms that myeloablative CR with ATG offers 95% DFS to SCA-patients and that stable MC in absence of SCA-symptoms does not require intervention such as DLI. It reports for the first time in HSCT for SCA that donor's age significantly increases GVHD risk, suggesting to choose the youngest sibling when possible, and that high ATG dose (20 mg/kg), which significantly reduces cGVHD risk without enhancing viral risk, should be recommended. Disclosures:Bernaudin:Novartis: Research Funding. Bertrand:ERYTECH Pharma: Principal Investigator Other. Gluckman:Cord use: Honoraria; gamida: Honoraria.